Netrins

ABSTRACT

Netrin proteins, nucleic acids which encode netrin proteins and hybridization reagents, probes and primers capable of hybridizing with netrin genes and methods for screening chemical libraries for lead compounds for pharmacological agents are provided.

RELATED APPLICATIONS

This is application is a continuation of and claims priority under35USC120 to Ser. No. 09/490,517, filed Jan. 25, 2000, now U.S. Pat. No.6,309,638, which is a continuation of and claims priority to Ser. No.08/482,677, filed Jun. 7, 1995, now U.S. Pat. No. 6,017,714, which is acontinuation-in-part and claims priority to Ser. No. 08/152,019, filedNov. 12, 1993, now U.S. Pat. No. 5,565,331, which are incorporatedherein by reference.

The research carried out in the subject application was supported inpart by grants from the National Institutes of Health. The governmentmay have rights in any patent issuing on this application.

INTRODUCTION

1. Field of the Invention

The field of this invention is vertebrate netrin proteins and geneswhich are involved in neural axon outgrowth.

2. Background

In the developing nervous system, axons project considerable distancesalong stereotyped pathways to reach their targets. Axon growth andguidance depends partly on the recognition of cell-surface andextracellular matrix cues along these pathways. The identification ofsuch nerve cell growth and guidance cues is the holy grail ofneurobiology. These are the compounds that tell neurons when to grow,where to grow, and when to stop growing. The medical applications ofsuch compounds are enormous and include modulating neuronal growthregenerative capacity, treating neurodegenerative disease, and mapping(e.g. diagnosing) genetic neurological defects.

Over decades of concentrated research, various hypotheses involvingchemo-attractants and repellents, labeled pathways, cell adhesionmolecules, etc. have been invoked to explain guidance. Molecules such asN-CAM and N-cadherin have been reported to provide favorable substratesfor axon growth and certain sensory axons may be responsive to NGF andNGF-like factors. Recent reports suggest the existence of diffusiblechemotropic molecule(s) which influence the pattern and orientation ofcommissural axon growth.

Relevant Literature

Placzek et al. (1990) Development 110, 19-30; Placzek et al. (1990) ColdSpring Harbor Symposia on Quantitative Biology 55, 279-302.; andTessier-Lavigne et al. (1988) Nature 336: 775-778 report evidence fordiffusible chemotropic molecules which influence the pattern andorientation of commissural axon growth. Gundersen and Barret (1980) JCB87, 546-554, Lohof et al. (1992) J. Neurosci. 12 (4), 1253-1261 andZheng et al. (1993) Soc. Neurosci. Abstr 19, 608.9 report neuralchemotaxis in response to NGF, cAMP and acetylcholine, respectively.Ishii et al. (1992) Neuron 9, 873-881 disclose a gene, unc-6, derivedfrom C. elegans, which has sequence similarity to the disclosed netrins.Data disclosed in this application was published in Serafini et al(1994) Cell 78, 409-424 and Kennedy et al (1994) Cell 78, 425-435 atpage 5, column 1. The work was also reported in The New York Times,Section B7, Tuesday, Aug. 16, 1994 and more recently (May 19, 1995)described in Science 268, 971-973 (see also references cited therein).

SUMMARY OF THE INVENTION

The invention provides methods and compositions relating to netrins andnetrin genes. Netrins are a novel class of proteins which are naturallyinvolved in neural axon guidance. The subject compositions includenucleic acids which encode netrin proteins and hybridization probes andprimers capable of hybridizing with netrin genes. Netrins findparticular use in modulating neural axon outgrowth. The disclosedcompositions also find use variously in screening chemical libraries forregulators of axon outgrowth and orientation, in genetic mapping, asprobes for related genes, as diagnostic reagents for geneticneurological disease and in the production of specific cellular andanimal systems for the development of neurological disease therapy.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods and compositions relating to netrins andnetrin genes; including methods and compositions for identifying,purifying, characterizing, and producing netrins and for identifying,characterizing, cloning, expressing, inhibiting the expression of andamplifying netrin genes.

Netrins are characterized by sequence similarity to the disclosednetrins 1 and 2. Using the amino acid sequence search program BLASTP(Altschul et al. (1990) Basic Local Alignment Search Tool, J Mol Biol215, 403-410), complete (full length) netrin amino acid sequencesprovide a Probability P(N) score of less than 1.0 e⁻²⁰⁰. In contrast,complete amino acid sequence comparison of a netrin with theevolutionarily related laminin proteins provides P(N) scores exceeding1.0 e⁻¹⁴⁴. In addition, netrins generally show at least about 25%overall pair-wise sequence identity with all of the disclosed netrins 1and 2 and at least about 50% pair-wise sequence identity within domainV. Furthermore, netrins are generally characterized by netrin-specificamino acid sequences invariant across the disclosed netrins 1 and 2 asseen in their amino acid alignments. The subject netrins may beincomplete translates of the disclosed netrin cDNA sequences or deletionmutants of the corresponding conceptual translates, which translates ordeletion mutants have the netrin binding activity and specificitydescribed herein.

Netrin peptides of the invention comprise unique portions of thedisclosed netrin polypeptides and netrin receptors. A “unique portion”has an amino acid sequence unique to that disclosed in that it is notfound in any previously known protein and has a length at least longenough to define a novel peptide. Unique portions are found to vary fromabout 5 to about 25 residues, preferably from 5 to 10 residues inlength, depending on the particular amino acid sequence and are readilyidentified by comparing the subject portion sequences with knownpeptide/protein sequence data bases. Preferred unique portions includenetrin residues that directly bind and activate (agonize) netrinreceptors, especially residues that derive from the EGF-like domains ofthe disclosed sequences, especially those of the human varieties.

Particular preferred netrin peptides are listed here. These peptides areshown by functional assays disclosed herein to have biological activityincluding axon outgrowth and/or orienting activity. It is apparent tothose of ordinary skill in the art that substitutions of chemicallyconservative residues can be made while preserving function.

Preferred peptides derived from domain V of netrin 2 and netrin 1: 1.NGH AA/SR (SEQ ID NO:04/06, residues 289-294/265-270) 2. VRD RDD N/SLV(SEQ ID NO:04, residues 296-304) 3. VKD KEQ KLV (SEQ ID NO:06, residues272-280) 4. KHN TE/AG PE (SEQ ID NO:04/06, residues 308-315/284-291) 5.KPF HYD DRP WQR AT/SA REA NE (SEQ ID NO:04/06, residues 320-338/296-319)6. NLH ARR (SEQ ID NO:04, residues 345-350) 7. RFN MEL YKL SGR KSG GV(SEQ ID NO:04/06, residues 352-368/328-344) 8. RHN TAG RH (SEQ IDNO:04/06, residues 373-380/349-356) 9. KEG FYR DLS KP/SIS/TH/DR KA (SEQID NO:04/06, residues 385-401/361-377) 10. HPV GAA GK/QT (SEQ IDNO:04/06, residues 408-416/384-392) 11. NQT TGQ (SEQ ID NO:04/06,residues 418-423/394-399) 12. KDG VTG I/LT (SEQ ID NO:04/06, residues427-434/403-410) 13. AKG Y/FQQ SRS PI/VA P (SEQ ID NO:04/06, residues439-451/415-427) Preferred peptides derived from the C terminal domainsof netrin 2 and netrin 1: 14. IKI PAI/AN/P (SEQ ID NO:04/06, residues453-459/429-435) 15. IKI PVR (SEQ ID NO:08, residues 451-456) 16. STEA/EPA DCD SYC K (SEQ ID NO:04/06, residues 466-478/442-454) 17. KI/MNMKK YCK/R KDY V/AVQ (SEQ ID NO:04/06, residues 485-499/461-475) 18. KFTI/VNI L/T/ISV YK (SEQ ID NO:04/06, residues 513-523/489-499) 19. CKCPKI/V (SEQ ID NO:04/06, residues 545-550/521-526) 20. ADK S/NSL VIQ WRD(SEQ ID NO:04/06, residues 573-584/549-560) 21. RLR RGD QTL W (SEQ IDNO:04, residues 528-537) 22. RVK RGD NFL W (SEQ ID NO:06, residues504-513) Preferred peptides derived from domain VI of netrin 2 andnetrin 1: 23. DPC YDE (SEQ ID NO:04/06, residues 40-45/27-30) 24. RCIPE/DF VNA/S AFG KEV (SEQ ID NO:04/06, residues 51-65/38-52) 25. SST CGKPP (SEQ ID NO:04/06, residues 68-75/55-62) 26. A/SSD PKR/K AHP PA/S (SEQID NO:04, residues 97-107) 27. LTD LNN PH (SEQ ID NO:04, residues109-116) 28. LTD LNT AA (SEQ ID NO:06, residues 80-87) 29. NL/MT CWR/QS-- (SEQ ID NO:04/06, residues 117-123/88-94)

The claimed netrins are isolated, partially pure or pure and aretypically recombinantly produced. An “isolated” protein for example, isunaccompanied by at least some of the material with which it isassociated in its natural state and constitutes at least about 0.5%,preferably at least about 2%, and more preferably at least about 5% byweight of the total protein in a given sample; a partially pure proteinconstitutes at least about 10%, preferably at least about 30%, and morepreferably at least about 60% by weight of the total protein in a givensample; and a pure protein constitutes at least about 70%, preferably atleast about 90%, and more preferably at least about 95% by weight of thetotal protein in a given sample. A wide variety of molecular andbiochemical methods are available for generating and expressing thesubject compositions, see e.g. Molecular Cloning, A Laboratory Manual(Sambrook, et al. Cold Spring Harbor Laboratory), Current Protocols inMolecular Biology (Eds. Aufubel, et al., Greene Publ. Assoc.,Wiley-Interscience, NY) or that are otherwise known in the art. Thedisclosed netrin peptides are also used as immunogens to generatespecific polyclonal or monoclonal antibodies. See, Harlow and Lane(1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory,for general methods.

The disclosed netrin compositions may be used to modulate axon outgrowthor guidance in situ or in vivo. For in vivo applications, thecompositions are added to a retained physiological fluid such as bloodor synovial fluid. For CNS administration, a variety of techniques areavailable for promoting transfer of the therapeutic across the bloodbrain barrier including disruption by surgery or injection drugs whichtransiently open adhesion contact between CNS vasculature endothelialcells, and compounds which facilitate translocation through such cells.Netrins may also be amenable to direct injection or infusion, topical,intratracheal/nasal administration e.g. through aerosol, intraocularly,or within/on implants e.g. fibers e.g. collagen, osmotic pumps, graftscomprising appropriately transformed cells, etc. A particular method ofadministration involves coating, imbedding or derivatizing fibers, suchas collagen fibers, protein polymers, etc. with therapeutic proteins.Other useful approaches are described in Otto et al. (1989) JNeuroscience Research 22, 83-91 and Otto and Unsicker (1990) JNeuroscience 10, 1912-1921. Generally, the amount administered will beempirically determined, typically in the range of about 10 to 1000 μg/kgof the recipient and the concentration will generally be in the range ofabout 50 to 500 μg/ml in the dose administered. Other additives may beincluded, such as stabilizers, bactericides, etc. will be present inconventional amounts.

The invention provides netrin-specific binding agents including isolatedbinding targets such as membrane-bound netrin receptors andnetrin-specific antibodies and binding agents identified in screens ofnatural and synthetic chemical libraries, and methods of identifying andmaking such agents, and their use in diagnosis, therapy andpharmaceutical development. Generally, netrin-specificity of the bindingagent is shown by binding equilibrium constants. Such agents are capableof selectively binding a netrin, i.e. with an equilibrium constant atleast about 10⁷ M⁻¹, preferably at least about 10⁸ M⁻¹, more preferablyat least about 10⁹ M⁻¹. A wide variety of cell-based and cell-freeassays may be used to demonstrate netrin-specific binding; preferred arerapid in vitro, cell-free assays such as mediating or inhibitingnetrin-cell/protein binding, immunoassays, etc.

The invention also provides nucleic acids encoding the subject proteins,which nucleic acids may be part of netrin-expression vectors and may beincorporated into recombinant cells for expression and screening,transgenic animals for functional studies (e.g. the efficacy ofcandidate drugs for neural disease or injury), etc. and nucleic acidhybridization probes and replication/amplification primers having anetrin cDNA specific sequence. The hybridization probes contain asequence common or complementary to the corresponding netrin genesufficient to make the probe capable of specifically hybridizing to thecorresponding netrin gene in the presence of laminin genes.Hybridization probes having in excess of 100 continuous bases of netringene sequence are generally capable of hybridizing to the correspondingnetrin cDNA and remaining bound at a reduced final wash stringency of0.2×SSC (0.9 M saline/0.09 M sodium citrate) and 0.1% SDS buffer at atemperature of 65° C.

Netrin genes, the term including natural genomic and mRNA/cDNAsequences, are characterized by sequence similarity to the disclosednetrin 1 and 2 cDNAs. Using the nucleic acid sequence search programBLASTX (Altschul et al. (1990) Basic Local Alignment Search Tool, J MolBiol 215, 403-410), complete coding region (full length) netrin cDNAsequences provide a Probability P(N) score of less than 1.0 e⁻²⁰⁰. Incontrast, complete coding region nucleic acid sequence comparison of anetrin cDNA with the evolutionarily related laminin cDNAs provides P(N)scores exceeding 1.0 e⁻¹⁴⁴. In addition, netrin cDNAs generally show atleast about 25% overall coding region pair-wise sequence identity withthe disclosed netrins 1 and 2 cDNAs and at least about 35% domain Vcoding region pair-wise sequence identity. Furthermore, netrin genes aregenerally characterized by netrin gene-specific nucleic acid sequencesinvariant across the disclosed netrin 1 and 2 cDNAs as seen in theirnucleic acid alignments. Vertebrate netrin genes derive fromvertebrates.

The subject nucleic acids are isolated, meaning they comprise a sequencejoined to a nucleotide other than that which it is joined to on anatural chromosome and usually constitutes at least about 0.5%,preferably at least about 2%, and more preferably at least about 5% byweight of total nucleic acid present in a given fraction. A partiallypure nucleic acid constitutes at least about 10%, preferably at leastabout 30%, and more preferably at least about 60% by weight of totalnucleic acid present in a given fraction. A pure nucleic acidconstitutes at least about 80%, preferably at least about 90%, and morepreferably at least about 95% by weight of total nucleic acid present ina given fraction. The subject nucleic acids find a wide variety ofapplications including use as translatable transcripts, hybridizationprobes, PCR primers, therapeutic nucleic acids, etc.; use in detectingthe presence of netrin genes and gene transcripts, in detecting oramplifying nucleic acids encoding other netrins, and in gene therapyapplications, e.g. antisense oligonucleotides capable of inhibiting theintracellular expression of a targeted netrin transcript.

The invention provides efficient methods of identifying pharmacologicalagents or lead compounds for agents capable of mimicking or modulatingnetrin function (e.g. bioactive netrin deletion mutants and netrinpeptides). A wide variety of screens may be used; for example,cell-based assays for may be used for monitoring netrin function and invitro binding assays may be used to identify netrin-specific bindingagents. Tessier-Lavigne et al. (1988, supra) describe an assay fornetrin activity and Kennedy et al. (1994) Cell 78, 425-435 describe aparticularly convenient COS cell-based netrin expression assay.Preferred methods are amenable to automated, cost-effective highthroughput screening of natural and synthetic chemical libraries forlead compounds. Identified reagents find use in the pharmaceuticalindustries for animal and human trials; for example, the reagents may bederivatized and rescreened in in vitro and in vivo assays to optimizeactivity and minimize toxicity for pharmaceutical development.

NETRIN GENE CLONING STRATEGIES

Vertebrate netrin genes are cloned using the using the two generalcloning strategies illustrated below for mouse and human netrins. First,using a strategy based on the initial amplification of a PCR product,oligonucleotide primers are designed using amino acid and nucleic acidsequences conserved among the previously identified vertebrate netrinsequences. Using these primers, a partial cDNA clone, corresponding tothe novel netrin of interest is amplified from cDNA ergonomic DNA fromthe tissue and organism of interest by PCR. This partial clone is thenused to generate a labeled probe which is used to screen a cDNA libraryor genomic library at high stringency to isolate a full length cDNAcorresponding to the clone of interest. We describe below how such astrategy, based on PCR followed by library screening, has been used tosuccessfully isolate mouse netrin-1,Drosophila netrin-a, and two humannetrin cDNAs. The second general strategy utilizes reduced stringencylibrary screening (Sambrook et al., 1989). We demonstrate below theapplicability of this method in the isolation of mouse netrin-2. In thiscase we amplified and incorporated ³²P into a probe which correspondedto domains VI and V in chicken netrin-2. Domains VI and V contain anumber of regions of sequence which are well conserved among allvertebrate netrin family members isolated to this date. This probe wasthen used to screen an embryonic mouse brain cDNA library at reducedstringency. Our cloning of mouse netrin-2 using this method demonstratesthat hybridization conditions are conveniently established which willdetect netrin sequences between vertebrate species while avoidingsignificant background hybridization to non-netrin clones.

Our data identify netrin sequences common to the vertebrate netrins,mouse netrin-1, chicken netrin-1, and chicken netrin-2, which are notshared by the invertebrate netrin unc-6 as seen in netrin sequencealignments. The presence of these sequences, specific to vertebrates andconserved in all vertebrate netrins isolated, provides the necessary andsufficient sequence informative for generating primers and/or probes forany vertebrate netrin gene. In addition, amino acid sequence alignmentssimilarly demonstrate that the vertebrate netrins define a structuralclass sharing common sequences not shared-with the invertebrate speciesillustrated by C. elegans unc-6 and the Drosophila Melanogasternetrin-a. Furthermore the alignment between the Drosophila and the C,elegans sequences indicates there is a greater diversity of netrin aminoacid sequence represented within the invertebrate phylum than is presentwithin the sequences derived from the vertebrate phylum.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

We isolated chicken netrin 1 and 2 cDNAs as described in Serafini et al.(1994) Cell 78:409-424. Based on the ckick netrin 1 and 2 cDNAsequences, we designed degenerate oligonucleotide primers and used theseprimers to amplify a cDNA encoding mouse netrin 1 from a murine cDNAlibrary.

We isolated a mouse netrin-2 cDNA from a screen of a P0 (day of birth)mouse brain cDNA library (stratagene 937319: mouse P0 brain cDNA libraryin ZAPXP, oriented cloning). The probe used corresponded to sequenceswithin domains VI and V of chicken netrin-2. Domain VI and V of thenetrins contain regions of nucleic acid and amino acid sequence highlyconserved in all netrins in each of the vertebrate species characterizedto this date. The probe was labeled by incorporation of ³²P during PCRusing a template of chicken netrin-2 cDNA.

1×10⁶ clones were screened at a reduced final wash stringency of 0.2×SSCand 0.1% SDS at 65 A1C (Sambrook et al., 1989). A single ˜7.5 kb clonecorresponding to mouse netrin-2 CDNA was obtained. Sequencing of thisCDNA indicated that it comprises over 40% of the netrin coding sequencebut is lacking sequence corresponding to the 5′ coding sequence of mousenetrin-2. To isolate the 5′ coding sequence from cDNA isolated from CDNAlibraries, we have employed a combination of library screening and PCRusing standard methods (Sambrook et al., 1989).

We first isolated a human netrin cDNA using the degenerateoligonucleotide primers. The primers were constructed using amino acidsequences conserved in the previously isolated chick and mouse netrinsequences as a guide. The starting material for PCR was 100 ng of humangenomic DNA. PCR products were subcloned and individual clonescontaining inserts corresponding to human netrin sequence isolated usinga Grunstein and Hogness screen (Sambrook, 1989). ³²P was incorporatedinto a probe using PCR with a portion of the mouse netrin-1 cDNA cloneas a template. The final wash of the filters was at a reduced stringencyof 1×SSC and 0.1%SDS at 65° C. (Sambrook et al., 1989). This screenisolated an approximately 140 base pair human netrin cDNA clone. ThiscDNA fragment was used to isolate a longer human netrin cDNA from aHuman fetal brain cDNA library (Stratagene cat#936206). The ˜140 basepair human netrin cDNA was used as a template and 32P incorporated intoa human netrin cDNA probe using PCR. 1×10⁶ clones were screened at highstringency (Sambrook et al., 1989) identifying a single approximately 7kb netrin cDNA. Sequence obtaining from the ends of this clone encodeuntranslated DNA sequence (see tables 9 and 10), indicating a fulllength clone. Internal sequence of the cDNA obtained usingoligonucleotide primers corresponding to sequences contained in the ˜140clone, confirm and extend that sequence in the larger clone. Searches ofthe NBRF amino acid and nucleic acid sequence databases indicate thatthe published sequences with which this human cDNA shares the highestsequence identity are those of chicken netrin-1 and chicken netrin-2,the only vertebrate netrin sequences contained in the database at thisdate. In addition, these sequences encode amino acid sequencesindicating that this clone represents a human netrin cDNA.

A partial cDNA was first amplified by PCR using non-degenerate primersdesigned using the codon usage for Drosophila as a guide. The particularsequences used were chosen on the basis of their conservation in theamino acid sequences of the invertebrate netrin gene unc-6 and thechicken netrin-1 and netrin-2 cDNAs. Nested PCR amplification wasperformed using 1 ng of total embryonic Drosophila cDNA as a template. Afull length cDNA corresponding to Drosophila melanogaster netrin-a wasthen isolated by screening a cDNA library at high stringency usingstandard methods (Sambrook et al., 1989).

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

                   #             SEQUENCE LISTING(1) GENERAL INFORMATION:    (iii) NUMBER OF SEQUENCES: 14(2) INFORMATION FOR SEQ ID NO: 1:      (i) SEQUENCE CHARACTERISTICS:          (A) LENGTH: 1839 base  #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: double           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #1: ATGATCACAT CAGTATTGCG CTATGTGCTA GCGCTCTACT TTTGTATGGG CA#TAGCTCAT     60GGAGCATACT TTTCACAGTT CTCCATGAGA GCCCCAGACC ATGATCCTTG CC#ATGATCAT    120ACTGGTCGAC CAGTTCGATG TGTTCCCGAG TTCATAAATG CTGCTTTTGG AA#AACCTGTT    180ATTGCTAGTG ATACATGCGG AACAAACCGA CCAGACAAGT ATTGTACTGT GA#AGGAGGGT    240CCGGATGGAA TTATCCGTGA GCAATGTGAC ACTTGTGATG CTAGAAACCA TT#TCCAATCC    300CATCCAGCCT CTCTTCTAAC TGATCTCAAT TCGATTGGAA ACATGACATG CT#GGGTTTCC    360ACTCCAAGTT TGAGCCCACA AAACGTTTCA CTCACTTTGT CACTCGGAAA AA#AGTTTGAG    420CTCACTTACG TCTCAATGCA CTTCTGTTCC CGTCTCCCAG ATTCAATGGC AC#TTTACAAG    480TCTGCTGACT TTGGAAAGAC CTGGACCCCG TTTCAATTCT ACTCCTCCGA AT#GTCGTCGT    540ATATTTGGCA GAGATCCCGA CGTGTCGATA ACAAAGTCAA ACGAGCAAGA AG#CCGTTTGT    600ACTGCCTCTC ATATAATGGG TCCAGGAGGA AACCGTGTAG CGTTCCCTTT TC#TAGAGAAC    660AGACCTTCTG CACAAAACTT CGAAAACTCG CCGGTGCTTC AGGATTGGGT CA#CCGCAACT    720GACATTAAAG TGGTGTTTTC AAGGCTTAGT CCAGATCAGG CTGAACTGTA TG#GCTTGTCT    780AACGATGTCA ATTCGTACGG AAACGAGACG GATGATGAAG TCAAACAACG TT#ACTTCTAC    840TCAATGGGAG AACTGGCAGT TGGTGGTCGC TGCAAATGTA ATGGTCACGC CA#GTAGATGC    900ATCTTTGACA AAATGGGCCG GTACACTTGT GACTGCAAGC ATAACACTGC CG#GAACTGAA    960TGCGAAATGT GCAAACCATT CCATTACGAT CGTCCATGGG GAAGAGCCAC CG#CAAATTCT   1020GCCAACTCAT GTGTCGCTTG CAACTGCAAC CAACACGCAA AGAGATGCCG AT#TCGATGCT   1080GAGCTCTTTA GACTAAGTGG CAACCGGTCA GGAGGAGTGT GCTTGAACTG TC#GTCATAAC   1140ACTGCTGGAA GAAATTGTCA TCTCTGCAAA CCAGGATTTG TCCGTGATAC TT#CTCTGCCA   1200ATGACACATC GGAAAGCTTG TAAAGCTTGT GGATGTCATC CAGTCGGATC AC#TTGGAAAA   1260AGCTGCAACC AATCATCGGG TCAGTGCGTC TGCAAGCCTG GAGTCACTGG AA#CAACCTGT   1320AATCGTTGTG CCAAAGGATA CCAACAAAGC CGTTCTACAG TTACTCCGTG TA#TCGAAATT   1380CCGACCAAAG CTGATTTCAT TGGATCATCA CATTCAGAAG AGCAAGATCA GT#GTTCGAAG   1440TGCAGAATTG TTCCGAAGAG ACTCAACCAG AAGAAGTTCT GCAAGCGGGA TC#ATGCTGTC   1500CAGATGGTTG TGGTCAGCCG TGAGATGGTT GATGGATGGG CCAAGTACAA GA#TTGTGGTT   1560GAATCAGTTT TCAAACGAGG CACCGAGAAC ATGCAACGTG GCGAAACATC AT#TGTGGATT   1620TCCCCTCAAG GTGTCATTTG CAAGTGCCCA AAGCTCCGCG TCGGACGCCG TT#ATCTCCTC   1680CTTGGTAAGA ATGATTCCGA TCACGAGCGC GATGGATTGA TGGTCAATCC AC#AGACTGTA   1740TTGGTGGAAT GGGAGGACGA TATTATGGAT AAGGTACTAC GCTTCTCGAA AA#AAGATAAA   1800 CTTGGACAAT GCCCAGAGAT TACGTCACAC AGATACTGA      #                   #  1839 (2) INFORMATION FOR SEQ ID NO: 2:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 612 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #2:Met Ile Thr Ser Val Leu Arg Tyr Val Leu Al #a Leu Tyr Phe Cys Met1               5    #                10   #                15Gly Ile Ala His Gly Ala Tyr Phe Ser Gln Ph #e Ser Met Arg Ala Pro            20       #            25       #            30Asp His Asp Pro Cys His Asp His Thr Gly Ar #g Pro Val Arg Cys Val        35           #        40           #        45Pro Glu Phe Ile Asn Ala Ala Phe Gly Lys Pr #o Val Ile Ala Ser Asp    50               #    55               #    60Thr Cys Gly Thr Asn Arg Pro Asp Lys Tyr Cy #s Thr Val Lys Glu Gly65                   #70                   #75                   #80Pro Asp Gly Ile Ile Arg Glu Gln Cys Asp Th #r Cys Asp Ala Arg Asn                85   #                90   #                95His Phe Gln Ser His Pro Ala Ser Leu Leu Th #r Asp Leu Asn Ser Ile            100       #           105       #           110Gly Asn Met Thr Cys Trp Val Ser Thr Pro Se #r Leu Ser Pro Gln Asn        115           #       120           #       125Val Ser Leu Thr Leu Ser Leu Gly Lys Lys Ph #e Glu Leu Thr Tyr Val    130               #   135               #   140Ser Met His Phe Cys Ser Arg Leu Pro Asp Se #r Met Ala Leu Tyr Lys145                 1 #50                 1 #55                 1 #60Ser Ala Asp Phe Gly Lys Thr Trp Thr Pro Ph #e Gln Phe Tyr Ser Ser                165   #               170   #               175Glu Cys Arg Arg Ile Phe Gly Arg Asp Pro As #p Val Ser Ile Thr Lys            180       #           185       #           190Ser Asn Glu Gln Glu Ala Val Cys Thr Ala Se #r His Ile Met Gly Pro        195           #       200           #       205Gly Gly Asn Arg Val Ala Phe Pro Phe Leu Gl #u Asn Arg Pro Ser Ala    210               #   215               #   220Gln Asn Phe Glu Asn Ser Pro Val Leu Gln As #p Trp Val Thr Ala Thr225                 2 #30                 2 #35                 2 #40Asp Ile Lys Val Val Phe Ser Arg Leu Ser Pr #o Asp Gln Ala Glu Leu                245   #               250   #               255Tyr Gly Leu Ser Asn Asp Val Asn Ser Tyr Gl #y Asn Glu Thr Asp Asp            260       #           265       #           270Glu Val Lys Gln Arg Tyr Phe Tyr Ser Met Gl #y Glu Leu Ala Val Gly        275           #       280           #       285Gly Arg Cys Lys Cys Asn Gly His Ala Ser Ar #g Cys Ile Phe Asp Lys    290               #   295               #   300Met Gly Arg Tyr Thr Cys Asp Cys Lys His As #n Thr Ala Gly Thr Glu305                 3 #10                 3 #15                 3 #20Cys Glu Asn Cys Lys Pro Phe His Tyr Asp Ar #g Pro Trp Gly Arg Ala                325   #               330   #               335Thr Ala Asn Ser Ala Asn Ser Cys Val Ala Cy #s Asn Cys Asn Gln His            340       #           345       #           350Ala Lys Arg Cys Arg Phe Asp Ala Glu Leu Ph #e Arg Leu Ser Gly Asn        355           #       360           #       365Arg Ser Gly Gly Val Cys Leu Asn Cys Arg Hi #s Asn Thr Ala Gly Arg    370               #   375               #   380His Cys His Leu Cys Lys Pro Gly Phe Val Ar #g Asp Thr Ser Leu Pro385                 3 #90                 3 #95                 4 #00Met Thr His Arg Lys Ala Cys Lys Ser Cys Gl #y Cys His Pro Val Gly                405   #               410   #               415Ser Leu Gly Lys Ser Cys Asn Gln Ser Ser Gl #y Gln Cys Val Cys Lys            420       #           425       #           430Pro Gly Val Thr Gly Thr Thr Cys Asn Arg Cy #s Ala Lys Gly Tyr Gln        435           #       440           #       445Gln Ser Arg Ser Thr Val Thr Pro Cys Ile Ly #s Ile Pro Thr Lys Ala    450               #   455               #   460Asp Phe Ile Gly Ser Ser His Ser Glu Glu Gl #n Asp Gln Cys Ser Lys465                 4 #70                 4 #75                 4 #80Cys Arg Ile Val Pro Lys Arg Leu Asn Gln Ly #s Lys Phe Cys Lys Arg                485   #               490   #               495Asp His Ala Val Gln Met Val Val Val Ser Ar #g Glu Met Val Asp Gly            500       #           505       #           510Trp Ala Lys Tyr Lys Ile Val Val Glu Ser Va #l Phe Lys Arg Gly Thr        515           #       520           #       525Glu Asn Met Gln Arg Gly Glu Thr Ser Leu Tr #p Ile Ser Pro Gln Gly    530               #   535               #   540Val Ile Cys Lys Cys Pro Lys Leu Arg Val Gl #y Arg Arg Tyr Leu Leu545                 5 #50                 5 #55                 5 #60Leu Gly Lys Asn Asp Ser Asp His Glu Arg As #p Gly Leu Met Val Asn                565   #               570   #               575Pro Gln Thr Val Leu Val Glu Trp Glu Asp As #p Ile Met Asp Lys Val            580       #           585       #           590Leu Arg Phe Ser Lys Lys Asp Lys Leu Gly Gl #n Cys Pro Glu Ile Thr        595           #       600           #       605 Ser His Arg Tyr    610 (2) INFORMATION FOR SEQ ID NO: 3:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 1921 base #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: double           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #3: ATGCCGCGGA GGGGCGCGGA GGGGCCGCTC GCCCTGCTGC TGGCGGCCGC GT#GGCTGGCA     60CAGCCGCTGC GAGGCGGCTA CCCCCTGAAC ATGTTCGCCG TGCAGACGCA GC#CGACCCCT    120GCTACGACGA GCACGGGCTG CCCCCCGCTG CATCCCGGAC TTCGTCAACT CG#GCCTTCGG    180CAAGGAGGTG AAGGTGTCGA GCACCTGCGG GAAGCCGCCG TCGAGGTACT GC#GTGGTGAC    240GGAGAAGGGC GAGGAGCAGG TCCGCTCGTG CCACCTCTGC AACGCCTCCG AC#CCCAAGCG    300CGCCCACCCG CCCTCCTTCC TCACCGACCT CAACAACCCG CACAACCTGA CG#TGCTGGCA    360GTCCGACAGC TACGTGCAGT ACCCGCACAA CGTCACCCTC ACGCTGTCCC TC#GGCAAGAA    420GTTCGAGGTG ACCTACGTGA GCCTGCAGTT CTGCTCGCCG CGCCCCGAGT CC#ATGGCCAT    480CTACAAGTCC ATGGACTACG GCAAGACGTG GGTGCCCTTC CAGTTCTACT CC#ACGCAGTG    540CCGCAAGATG TACAACAAGC CGAGCCGCGC CGCCATCACC AAGCAGAACG AG#CAGGAGGC    600CATCTGCACC GACTCGCACA CCGACGTGCG GCCCCTCTCC GGCGGCCTCA TC#GCCTTCAG    660CACCCTGGAC GGCCGCCCCA CCGCCCACGA CTTCGACAAC TCGCCCGTGC TG#CAGGACTG    720GGTGACGGCC ACCGACATCA AGGTGACCTT CAGCCGCCTG CACACCTTCG GC#GACGAGAA    780CGAGGACGAC TCCGAGCTCG CCCGCGACTC CTACTTCTAC GCCGTGTCCG AC#CTGCAGGT    840CGGCGGGCGC TGCAAGTGCA ACGGGCACGC GTCCCGCTGC GTCCGCGACC GC#GACGACAA    900CCTGGTGTGC GACTGCAAGC ACAACACGGC CGGGCCCGAG TGCGACCGCT GC#AAACCCTT    960CCACTACGAC CGGCCCTGGC AGAGGGCGAC CGCCCGAGAG GCCAACGAGT GC#GTGGCCTG   1020CAACTGCAAC CTGCATGCAC GGCGCTGCCG CTTCAACATG GAGCTGTACA AG#CTGTCGGG   1080CAGAAAGAGC GGCGGTGTCT GCCTCAACTG CCGGCACAAC ACGGCCGGGC GG#CACTGCCA   1140CTACTGCAAG GAAGGCTTCT ACCGCGACCT CAGCAAACCC ATCTCCCACC GC#AAGGCCTG   1200CAAAGAGTGC GATTGCCATC CCGTGGGCGC CGCCGGCCAA ACCTGCAACC AA#ACCACGGG   1260GCAGTGTCCA TGCAAGGACG GCGTCACCGG CATCACCTGC AACCGCTGCG CC#AAGGGCTA   1320CCAGCAGAGC CGCTCGCCCA TTGCCCCCTG CATAAAGATC CCCGCCGCGC CG#CCCCCCAC   1380AGCTGCCAGC AGCACGGAGG AGCCTGCAGA CTGTGACTCG TACTGCAAAG CC#TCCAAGGG   1440GAAGCTGAAG ATCAACATGA AGAAGTACTG CAAGAAGGAC TACGCTGTGC AG#ATCCACAT   1500CCTGAAAGCG GAAAAAAATG CCGACTGGTG GAAGTTCACC GTCAACATCA TC#TCTGTCTA   1560CAAACAGGGC AGCAACCGGC TGCGGCGCGG GGACCAGACC CTGTGGGTGC AC#GCCAAGGA   1620CATCGCCTGC AAGTGCCCCA AGGTGAAGCC CATGAAGAAG TACCTCCTGC TG#GGCAGCAC   1680CGAGGACTCT CCCGACCAGA GCGGCATCAT CGCGGACAAG AGCAGCCTGG TG#ATCCAATG   1740GCGGGACACG TGGGCACGGC GGCTGCGGAA GTTCCAGCAG AGGGAGAAGA AG#GGGAAGTG   1800TAGGAAGGCG TAGGGAGGAG CGGTGATGGA CTGAGCGCTG CCGGGTGCGG GC#GGGGGGTG   1860GGCGCAGGGG GCTCACGGCA TCTCGTATTG AGGGATGGAA GGGGAAAAAA AA#CACGAAAC   1920 C                   #                  #                   #             1921 (2) INFORMATION FOR SEQ ID NO: 4:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 605 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #4:Met Pro Arg Arg Gly Ala Glu Gly Pro Leu Al #a Leu Leu Leu Ala Ala1               5    #                10   #                15Ala Trp Leu Ala Gln Pro Leu Arg Gly Gly Ty #r Pro Xaa Leu Asn Met            20       #            25       #            30Phe Ala Val Gln Thr Xaa Ala Asp Pro Cys Ty #r Asp Glu His Gly Leu        35           #        40           #        45Pro Xaa Arg Cys Ile Pro Asp Phe Val Asn Se #r Ala Phe Gly Lys Glu    50               #    55               #    60Val Lys Val Ser Ser Thr Cys Gly Lys Pro Pr #o Ser Arg Tyr Cys Val65                   #70                   #75                   #80Val Thr Glu Lys Gly Glu Glu Gln Val Arg Se #r Cys His Leu Cys Asn                85   #                90   #                95Ala Ser Asp Pro Lys Arg Ala His Pro Pro Se #r Phe Leu Thr Asp Leu            100       #           105       #           110Asn Asn Pro His Asn Leu Thr Cys Trp Gln Se #r Asp Ser Tyr Val Gln        115           #       120           #       125Tyr Pro His Asn Val Thr Leu Thr Leu Ser Le #u Gly Lys Lys Phe Glu    130               #   135               #   140Val Thr Tyr Val Ser Leu Gln Phe Cys Ser Pr #o Arg Pro Glu Ser Met145                 1 #50                 1 #55                 1 #60Ala Ile Tyr Lys Ser Met Asp Tyr Gly Lys Th #r Trp Val Pro Phe Gln                165   #               170   #               175Phe Tyr Ser Thr Gln Cys Arg Lys Met Tyr As #n Lys Pro Ser Arg Ala            180       #           185       #           190Ala Ile Thr Lys Gln Asn Glu Gln Glu Ala Il #e Cys Thr Asp Ser His        195           #       200           #       205Thr Asp Val Arg Pro Leu Ser Gly Gly Leu Il #e Ala Phe Ser Thr Leu    210               #   215               #   220Asp Gly Arg Pro Thr Ala His Asp Phe Asp As #n Ser Pro Val Leu Gln225                 2 #30                 2 #35                 2 #40Asp Trp Val Thr Ala Thr Asp Ile Lys Val Th #r Phe Ser Arg Leu His                245   #               250   #               255Thr Phe Gly Asp Glu Asn Glu Asp Asp Ser Gl #u Leu Ala Arg Asp Ser            260       #           265       #           270Tyr Phe Tyr Ala Val Ser Asp Leu Gln Val Gl #y Gly Arg Cys Lys Cys        275           #       280           #       285Asn Gly His Ala Ser Arg Cys Val Arg Asp Ar #g Asp Asp Asn Leu Val    290               #   295               #   300Cys Asp Cys Lys His Asn Thr Ala Gly Pro Gl #u Cys Asp Arg Cys Lys305                 3 #10                 3 #15                 3 #20Pro Phe His Tyr Asp Arg Pro Trp Gln Arg Al #a Thr Ala Arg Glu Ala                325   #               330   #               335Asn Glu Cys Val Ala Cys Asn Cys Asn Leu Hi #s Ala Arg Arg Cys Arg            340       #           345       #           350Phe Asn Met Glu Leu Tyr Lys Leu Ser Gly Ar #g Lys Ser Gly Gly Val        355           #       360           #       365Cys Leu Asn Cys Arg His Asn Thr Ala Gly Ar #g His Cys His Tyr Cys    370               #   375               #   380Lys Glu Gly Phe Tyr Arg Asp Leu Ser Lys Pr #o Ile Ser His Arg Lys385                 3 #90                 3 #95                 4 #00Ala Cys Lys Glu Cys Asp Cys His Pro Val Gl #y Ala Ala Gly Gln Thr                405   #               410   #               415Cys Asn Gln Thr Thr Gly Gln Cys Pro Cys Ly #s Asp Gly Val Thr Gly            420       #           425       #           430Ile Thr Cys Asn Arg Cys Ala Lys Gly Tyr Gl #n Gln Ser Arg Ser Pro        435           #       440           #       445Ile Ala Pro Cys Ile Lys Ile Pro Ala Ala Pr #o Pro Pro Thr Ala Ala    450               #   455               #   460Ser Ser Thr Glu Glu Pro Ala Asp Cys Asp Se #r Tyr Cys Lys Ala Ser465                 4 #70                 4 #75                 4 #80Lys Gly Lys Leu Lys Ile Asn Met Lys Lys Ty #r Cys Lys Lys Asp Tyr                485   #               490   #               495Ala Val Gln Ile His Ile Leu Lys Ala Glu Ly #s Asn Ala Asp Trp Trp            500       #           505       #           510Lys Phe Thr Val Asn Ile Ile Ser Val Tyr Ly #s Gln Gly Ser Asn Arg        515           #       520           #       525Leu Arg Arg Gly Asp Gln Thr Leu Trp Val Hi #s Ala Lys Asp Ile Ala    530               #   535               #   540Cys Lys Cys Pro Lys Val Lys Pro Met Lys Ly #s Tyr Leu Leu Leu Gly545                 5 #50                 5 #55                 5 #60Ser Thr Glu Asp Ser Pro Asp Gln Ser Gly Il #e Ile Ala Asp Lys Ser                565   #               570   #               575Ser Leu Val Ile Gln Trp Arg Asp Thr Trp Al #a Arg Arg Leu Arg Lys            580       #           585       #           590Phe Gln Gln Arg Glu Lys Lys Gly Lys Cys Ar #g Lys Ala        595           #       600           #       605(2) INFORMATION FOR SEQ ID NO: 5:      (i) SEQUENCE CHARACTERISTICS:          (A) LENGTH: 2779 base  #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: double           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #5: TCCTGCGCCT GCTGCTCACC ACCAGCGTGC TCCGCCTGGC ACGAGCTGCA AA#CCCCTTCG     60TGGCTCAGCA GACTCCCCCA GACCCCTGCT ACGATGAGAG CGGGGCTCCC CC#GCGCTGCA    120TCCCCGAGTT CGTCAACGCC GCCTTTGGGA AGGAGGTGCA GGCTTCCAGC AC#CTGTGGGA    180AGCCCCCAAC ACGGCACTGC GATGCCTCGG ACCCCCGCCG AGCCCACCCA CC#CGCCTACC    240TGACCGACCT CAACACCGCC GCCAACATGA CGTGCTGGCG CTCCGAGACC CT#GCACCACC    300TGCCCCACAA CGTCACCCTC ACCCTTTCCC TCGGCAAGAA GTTTGAGGTG GT#CTACGTCA    360GCCTCCAGTT CTGCTCGCCC CGGCCGGAGT CCACCGCCAT CTTCAAGTCC AT#GGACTACG    420GCAAGACGTG GGTCCCCTAC CAGTACTACT CCTCGCAGTG CCGCAAGATC TA#CGGCAAGC    480CCAGCAAGGC CACCGTCACC AAGCAGAACG AGCAGGAGGC GCTGTGCACC GA#TGGCCTCA    540CCGACCTCTA CCCGCTCACT GGCGGCCTCA TCGCCTTCAG CACGCTCGAC GG#GCGGCCCT    600CGGCCCAGGA CTTCGACAGC AGCCCTGTGC TGCAGGACTG GGTGACGGCC AC#CGACATCC    660GGGTGGTGTT CAGCCGTCCC CACCTCTTCC GCGAGCTGGG GGGCCGCGAG GC#TGGCGAGG    720AGGACGGGGG GGCCGGGGCC ACCCCCTACT ACTACTCGGT GGGCGAGCTG CA#GGTCGGCG    780GGCGCTGCAA GTGCAACGGG CACGCCTCGC GCTGCGTCAA GGACAAGGAG CA#GAAGCTGG    840TGTGTGACTG CAAGCACAAC ACCGAGGGGC CCGAGTGCGA CCGCTGCAAG CC#CTTCCACT    900ACGACCGGCC GTGGCAGCGG GCCAGCGCCC GCGAGGCCAA CGAGTGCCTG GC#CTGCAACT    960GCAACCTGCA CGCTCGGCGC TGCCGCTTCA ACATGGAGCT GTATAAGCTG TC#CGGCAGGA   1020AGAGCGGCGG CGTTTGCCTC AACTGCCGAC ACAACACGGC TGGGAGGCAC TG#CCACTACT   1080GCAAGGAGGG CTTCTACCGG GACCTCAGCA AGTCCATCAC GGACCGCAAG GC#CTGCAAAG   1140CCTGTGACTG CCACCCAGTT GGTGCTGCTG GCAAGACCTG CAACCAAACA AC#AGGGCAGT   1200GCCCGTGCAA GGACGGCGTG ACCGGCCTCA CCTGCAACCG CTGCGCCAAG GG#CTTCCAGC   1260AGAGCCGCTC GCCTGTGGCC CCCTGCATCA AGATCCCTGC CATCAACCCG AC#CTCTCTTG   1320TCACCAGCAC GGAGGCACCT GCAGACTGTG ACTCCTACTG CAAGCCAGCC AA#AGGCAACT   1380ACAAGATTAA CATGAAGAAG TACTGCAAGA AGGATTACGT GGTCCAAGTG AA#CATTTTGG   1440AAATGGAGAC GGTGGCCAAC TGGGCCAAGT TCACCATCAA CATCCTCTCT GT#CTACAAGT   1500GCCGCGACGA GCGGGTCAAG CGCGGAGACA ACTTCTTGTG GATCCACCTC AA#GGACCTGT   1560CCTGCAAGTG CCCCAAAATC CAGATCAGCA AGAAGTACCT GGTGATGGGC AT#CAGCGAGA   1620ACTCCACCGA CCGGCCGGGA CTGATGGCCG ACAAGAACAG CCTGGTCATC CA#GTGGAGGG   1680ACGCCTGGAC TCGCCGCCTT CGGAAACTGC AGCGGAGGGA GAAGAAAGGG AA#GTGTGTGA   1740AGCCCTGAGG GCCTCGTGCC CCACGCGGGT CCCGGCCCCA CTGCACACGC AG#ACCATGCC   1800CAGAGACTCT GTACATACAT ATCGTGTGAA CGGACTCTTC TGTCTATAGT GT#ATATTTTG   1860GCAACGGTTC CCCTTTTTGT GTGCGTGTGC ACGCGTGGGT GTGTGCACGT GT#GTGTGCGT   1920GTGTGTGTGT GTGTGTGTGT GTGTCTCCTC TCAGTGTGTA TTAAAAATAA GG#CGGTAATG   1980ACAAACCTTT AATGAGGAGC AAAGCAGAGG GGGTCCTGTG GGTGCCTGCT GC#CTGAAGGA   2040GCTTGAGGGG CTGGTTTCTT GCTCCGGGCG TGCTGTTCCT CACCCTTCTG TC#CTACTCTC   2100TCTTTCCCCT TGAGCAAAAC CTTCTGCCCA GTGCTGCTGT CTGAGCTCGC GG#CTCTCCCT   2160GCTGCAGAGC CCGGTCCCTC TCACGTGCTG CACATGTGCT GCTCTCAGCT CT#CTGTGCCC   2220CTTTTCTTGT GCAGCAGAGA CGGGAGGTCG GTTTCCTCCA TCCCGCTGCA CA#CACGGACC   2280GGCTGGGTGG AGACCATCCA GCGCTGCAGG ACCGGCCCCA GGAGCTCCGC TG#GGAGAACC   2340AAGTGACCTT TCTCCAGGCC TGATCCTGCA GGACCTCAGC TTTACATGGA CT#GGTCGTGC   2400CGCCCAGGGG CAGGGCCCAT GGAAGTCTTG GGGACAGCCA GGGCTGTTGG CC#ACCACCCC   2460ACAGAGCTGT TCTGAGCAGG GCGCAGGGGT CTGCCTGTCC TGGTGCGTGG TC#CAGGTGAC   2520CCACAGGAAA GACCTGCAGA TACCCATATT CTCCTCTCGT GCCAGCTCTG CA#TGCTGCTG   2580TGACCTTGGC CGTGCCAGAG GTGCAGAGGC AGAGGTGGCA GGAAGAGAGG AG#AGCTTTCG   2640CTGACCAACC TCCAGTCTTT CATTTCTTCT CATACTGTAT TAGTCTCCAG TT#CAAACAGA   2700CATCAGTTTC TTTCCACGTT GAGGTTATAG TGGTCTCGAG TAATAAACAT GA#ATGGAAAT   2760 AATAAAAAAA AAAAAAAAA              #                  #                 277 #9 (2) INFORMATION FOR SEQ ID NO: 6:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 581 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #6:Leu Arg Leu Leu Leu Thr Thr Ser Val Leu Ar #g Leu Ala Arg Ala Ala1               5    #                10   #                15Asn Pro Phe Val Ala Gln Gln Thr Pro Pro As #p Pro Cys Tyr Asp Glu            20       #            25       #            30Ser Gly Ala Pro Pro Arg Cys Ile Pro Glu Ph #e Val Asn Ala Ala Phe        35           #        40           #        45Gly Lys Glu Val Gln Ala Ser Ser Thr Cys Gl #y Lys Pro Pro Thr Arg    50               #    55               #    60His Cys Asp Ala Ser Asp Pro Arg Arg Ala Hi #s Pro Pro Ala Tyr Leu65                   #70                   #75                   #80Thr Asp Leu Asn Thr Ala Ala Asn Met Thr Cy #s Trp Arg Ser Glu Thr                85   #                90   #                95Leu His His Leu Pro His Asn Val Thr Leu Th #r Leu Ser Leu Gly Lys            100       #           105       #           110Lys Phe Glu Val Val Tyr Val Ser Leu Gln Ph #e Cys Ser Pro Arg Pro        115           #       120           #       125Glu Ser Thr Ala Ile Phe Lys Ser Met Asp Ty #r Gly Lys Thr Trp Val    130               #   135               #   140Pro Tyr Gln Tyr Tyr Ser Ser Gln Cys Arg Ly #s Ile Tyr Gly Lys Pro145                 1 #50                 1 #55                 1 #60Ser Lys Ala Thr Val Thr Lys Gln Asn Glu Gl #n Glu Ala Leu Cys Thr                165   #               170   #               175Asp Gly Leu Thr Asp Leu Tyr Pro Leu Thr Gl #y Gly Leu Ile Ala Phe            180       #           185       #           190Ser Thr Leu Asp Gly Arg Pro Ser Ala Gln As #p Phe Asp Ser Ser Pro        195           #       200           #       205Val Leu Gln Asp Trp Val Thr Ala Thr Asp Il #e Arg Val Val Phe Ser    210               #   215               #   220Arg Pro His Leu Phe Arg Glu Leu Gly Gly Ar #g Glu Ala Gly Glu Glu225                 2 #30                 2 #35                 2 #40Asp Gly Gly Ala Gly Ala Thr Pro Tyr Tyr Ty #r Ser Val Gly Glu Leu                245   #               250   #               255Gln Val Gly Gly Arg Cys Lys Cys Asn Gly Hi #s Ala Ser Arg Cys Val            260       #           265       #           270Lys Asp Lys Glu Gln Lys Leu Val Cys Asp Cy #s Lys His Asn Thr Glu        275           #       280           #       285Gly Pro Glu Cys Asp Arg Cys Lys Pro Phe Hi #s Tyr Asp Arg Pro Trp    290               #   295               #   300Gln Arg Ala Ser Ala Arg Glu Ala Asn Glu Cy #s Leu Ala Cys Asn Cys305                 3 #10                 3 #15                 3 #20Asn Leu His Ala Arg Arg Cys Arg Phe Asn Me #t Glu Leu Tyr Lys Leu                325   #               330   #               335Ser Gly Arg Lys Ser Gly Gly Val Cys Leu As #n Cys Arg His Asn Thr            340       #           345       #           350Ala Gly Arg His Cys His Tyr Cys Lys Glu Gl #y Phe Tyr Arg Asp Leu        355           #       360           #       365Ser Lys Ser Ile Thr Asp Arg Lys Ala Cys Ly #s Ala Cys Asp Cys His    370               #   375               #   380Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gl #n Thr Thr Gly Gln Cys385                 3 #90                 3 #95                 4 #00Pro Cys Lys Asp Gly Val Thr Gly Leu Thr Cy #s Asn Arg Cys Ala Lys                405   #               410   #               415Gly Phe Gln Gln Ser Arg Ser Pro Val Ala Pr #o Cys Ile Lys Ile Pro            420       #           425       #           430Ala Ile Asn Pro Thr Ser Leu Val Thr Ser Th #r Glu Ala Pro Ala Asp        435           #       440           #       445Cys Asp Ser Tyr Cys Lys Pro Ala Lys Gly As #n Tyr Lys Ile Asn Met    450               #   455               #   460Lys Lys Tyr Cys Lys Lys Asp Tyr Val Val Gl #n Val Asn Ile Leu Glu465                 4 #70                 4 #75                 4 #80Met Glu Thr Val Ala Asn Trp Ala Lys Phe Th #r Ile Asn Ile Leu Ser                485   #               490   #               495Val Tyr Lys Cys Arg Asp Glu Arg Val Lys Ar #g Gly Asp Asn Phe Leu            500       #           505       #           510Trp Ile His Leu Lys Asp Leu Ser Cys Lys Cy #s Pro Lys Ile Gln Ile        515           #       520           #       525Ser Lys Lys Tyr Leu Val Met Gly Ile Ser Gl #u Asn Ser Thr Asp Arg    530               #   535               #   540Pro Gly Leu Met Ala Asp Lys Asn Ser Leu Va #l Ile Gln Trp Arg Asp545                 5 #50                 5 #55                 5 #60Ala Trp Thr Arg Arg Leu Arg Lys Leu Gln Ar #g Arg Glu Lys Lys Gly                565   #               570   #               575Lys Cys Val Lys Pro             580 (2) INFORMATION FOR SEQ ID NO: 7:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 1811 base #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: double           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #7: ATGATGCGCG CTGTGTGGGA GGCGCTGGCG GCGCTGGCGG CGGTGGCGTG CC#TGGTGGGC     60GCGGTCCGCG GGCCCGGGCT TAGCATGTTC GCCGGCCAGG CGGCGCAGCC TG#ATCCTTGC    120TCGGATGAGA ATGGACACCC GCGCCGCTGC ATCCCGGACT TTGTCAACGC CG#CCTTCGGC    180AAGGACGTGC GCGTGTCCAG CACCTGCGGC CGGCCCCCGG CGCGCTACTG CG#TGGTGAGC    240GAGCGTGGTG AAGAGCGCGT GCGCTCCTGT CACCTCTGCA ACTCTTCGGA TC#CCAAGAAA    300GCGCACCCGC CCGCCTTCCT CACCGACCTC AATAACCCGC ACAACCTGAC GT#GCTGGCAG    360TCCGAGAACT ACCTGCAGTT CCCGCACAAC GTGACGCTCA CTCTGTCGCT CG#GCAAGAAG    420TTTGAGGTGA CCTATGTGAG CCTGCAATTC TGCTCGCCGC GGCCAGAGTC CA#TGGCCATC    480TACAAGTCCA TGGACTACGG GCGCACGTGG GTGCCCTTCC AGTTCTATTC CA#CGCAGTGC    540CGCAAAATGT ACAACCGGCC GCACCGCGCG CCTATCACCA AACAGAACGA GC#AGGAGGCC    600GTGTGCACCG ACTCGCACAC CGACATGCGC CCGCTCTCTG GCGGGCTGAT CG#CTTTCAGC    660ACGCTGGACG GGCGGCCCTC GGCGCACGAC TTCGACAACT CGCCGGTGCT GC#AGGACTGG    720GTCACGGCCA CCGACATCCG CGTGGCTTTC AGCCGCCTGC ACACGTTCGG CG#ACGAGAAC    780GAAGACGACT CGGAGCTGGC GCGCGACTCC TATTACTATG CAGTGTCTGA CC#TGCAGGTT    840GGCGGCCGCT GCAAGTGCAA CGGCCACGCG GCGCGTTGCG TGCGCGACCG AG#ACGACAGT    900CTGGTGTGTG ACTGTAGGCA CAACACGGCC GGCCCTGAAT GCGACCGTTG CA#AGCCCTTC    960CACTACGACC GGCCCTGGCA GCGCGCCACG GCCCGCGAGG CCAACGAGTG CG#TGGCCTGC   1020AACTGCAACC TCCATGCTCG GCGCTGCAGA TTCAACATGG AGCTCTATAA GC#TATCAGGG   1080CGCAAGAGCG GGGGAGTTGT CTCAACTGCC GCCACAACAC TGCGGGCCGC CA#CTGCCACT   1140ACTGCAAGGA GGGCTTCTAC CGAGACATGG GCAAGCCTAT CACCCACCGG AA#GGCTTGCA   1200AAGCCTGTGA TTGCCACCCA GTGGGTGCTG CTGGCAAGAC CTGCAATCAA AC#CACTGGCC   1260AATGTCCCTG CAAGGACGGC GTGACGGGCA TCACCTGCAA CCGATGTGCC AA#AGGCTACC   1320AGCAGAGCCG TTCCCCCATC GCCCCTTGCA TCAAGATTCC TGTGGCGCCG CC#CACCACTG   1380CAGCCAGCAG CGTGGAGGAA CCGGAAGACT GTGATTCCTA TTGCAAGGCC TC#CAAAGGCA   1440AGCTGAAGAT GAACATGAAG AAATACTGCA GGAAGGACTA TGCTGTCCAG AT#CCACATCC   1500TGAAGGCCGA CAAAGCAGGG GACTGGTGGA AGTTCACCGT GAACATCATC TC#CGTGTACA   1560AGCAGGGCAC AAGTCGTATT CGCCGTGGTG ACCAGAGTTT GTGGATCCGC TC#ACGAGACA   1620TCGCCTGCAA GTGTCCCAAA ATCAAGCCCC TCAAGAAGTA CTTGCTGTTG GG#TAATGCCG   1680AGGACTCACC TGACCAGAGT GGCATCGTGG CAGACAAGAG CAGCCTGGTG AT#CCAGTGGC   1740GGGACACATG GGCACGGCGG CTGCGCAAGT TCCAGCAACG GGAGAAGAAG GG#CAAGTGCA   1800 AGAAGGCCTA G                #                  #                   #     1811 (2) INFORMATION FOR SEQ ID NO: 8:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 603 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #8:Met Met Arg Ala Val Trp Glu Ala Leu Ala Al #a Leu Ala Ala Val Ala1               5    #                10   #                15Cys Leu Val Gly Ala Val Arg Gly Pro Gly Le #u Ser Met Phe Ala Gly            20       #            25       #            30Gln Ala Ala Gln Pro Asp Pro Cys Ser Asp Gl #u Asn Gly His Pro Arg        35           #        40           #        45Arg Cys Ile Pro Asp Phe Val Asn Ala Ala Ph #e Gly Lys Asp Val Arg    50               #    55               #    60Val Ser Ser Thr Cys Gly Arg Pro Pro Ala Ar #g Tyr Cys Val Val Ser65                   #70                   #75                   #80Glu Arg Gly Glu Glu Arg Val Arg Ser Cys Hi #s Leu Cys Asn Ser Ser                85   #                90   #                95Asp Pro Lys Lys Ala His Pro Pro Ala Phe Le #u Thr Asp Leu Asn Asn            100       #           105       #           110Pro His Asn Leu Thr Cys Trp Gln Ser Glu As #n Tyr Leu Gln Phe Pro        115           #       120           #       125His Asn Val Thr Leu Thr Leu Ser Leu Gly Ly #s Lys Phe Glu Val Thr    130               #   135               #   140Tyr Val Ser Leu Gln Phe Cys Ser Pro Arg Pr #o Glu Ser Met Ala Ile145                 1 #50                 1 #55                 1 #60Tyr Lys Ser Met Asp Tyr Gly Arg Thr Trp Va #l Pro Phe Gln Phe Tyr                165   #               170   #               175Ser Thr Gln Cys Arg Lys Met Tyr Asn Arg Pr #o His Arg Ala Pro Ile            180       #           185       #           190Thr Lys Gln Asn Glu Gln Glu Ala Val Cys Th #r Asp Ser His Thr Asp        195           #       200           #       205Met Arg Pro Leu Ser Gly Gly Leu Ile Ala Ph #e Ser Thr Leu Asp Gly    210               #   215               #   220Arg Pro Ser Ala His Asp Phe Asp Asn Ser Pr #o Val Leu Gln Asp Trp225                 2 #30                 2 #35                 2 #40Val Thr Ala Thr Asp Ile Arg Val Ala Phe Se #r Arg Leu His Thr Phe                245   #               250   #               255Gly Asp Glu Asn Glu Asp Asp Ser Glu Leu Al #a Arg Asp Ser Tyr Tyr            260       #           265       #           270Tyr Ala Val Ser Asp Leu Gln Val Gly Gly Ar #g Cys Lys Cys Asn Gly        275           #       280           #       285His Ala Ala Arg Cys Val Arg Asp Arg Asp As #p Ser Leu Val Cys Asp    290               #   295               #   300Cys Arg His Asn Thr Ala Gly Pro Glu Cys As #p Arg Cys Lys Pro Phe305                 3 #10                 3 #15                 3 #20His Tyr Asp Arg Pro Trp Gln Arg Ala Thr Al #a Arg Glu Ala Asn Glu                325   #               330   #               335Cys Val Ala Cys Asn Cys Asn Leu His Ala Ar #g Arg Cys Arg Phe Asn            340       #           345       #           350Met Glu Leu Tyr Lys Leu Ser Gly Arg Lys Se #r Gly Gly Val Cys Leu        355           #       360           #       365Asn Cys Arg His Asn Thr Ala Gly Arg His Cy #s His Tyr Cys Lys Glu    370               #   375               #   380Gly Phe Tyr Arg Asp Met Gly Lys Pro Ile Th #r His Arg Lys Ala Cys385                 3 #90                 3 #95                 4 #00Lys Ala Cys Asp Cys His Pro Val Gly Ala Al #a Gly Lys Thr Cys Asn                405   #               410   #               415Gln Thr Thr Gly Gln Cys Pro Cys Lys Asp Gl #y Val Thr Gly Ile Thr            420       #           425       #           430Cys Asn Arg Cys Ala Lys Gly Tyr Gln Gln Se #r Arg Ser Pro Ile Ala        435           #       440           #       445Pro Cys Ile Lys Ile Pro Val Ala Pro Pro Th #r Thr Ala Ala Ser Ser    450               #   455               #   460Val Glu Glu Pro Glu Asp Cys Asp Ser Tyr Cy #s Lys Ala Ser Lys Gly465                 4 #70                 4 #75                 4 #80Lys Leu Lys Met Asn Met Lys Lys Tyr Cys Ar #g Lys Asp Tyr Ala Val                485   #               490   #               495Gln Ile His Ile Leu Lys Ala Asp Lys Ala Gl #y Asp Trp Trp Lys Phe            500       #           505       #           510Thr Val Asn Ile Ile Ser Val Tyr Lys Gln Gl #y Thr Ser Arg Ile Arg        515           #       520           #       525Arg Gly Asp Gln Ser Leu Trp Ile Arg Ser Ar #g Asp Ile Ala Cys Lys    530               #   535               #   540Cys Pro Lys Ile Lys Pro Leu Lys Lys Tyr Le #u Leu Leu Gly Asn Ala545                 5 #50                 5 #55                 5 #60Glu Asp Ser Pro Asp Gln Ser Gly Ile Val Al #a Asp Lys Ser Ser Leu                565   #               570   #               575Val Ile Gln Trp Arg Asp Thr Trp Ala Arg Ar #g Leu Arg Lys Phe Gln            580       #           585       #           590Gln Arg Glu Lys Lys Gly Lys Cys Lys Lys Al #a         595          #       600 (2) INFORMATION FOR SEQ ID NO: 9:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 1743 base #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: double           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: DNA (genomic)    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #9:ATGCCCACCT GGCTCTGGGG GCTGCTGCTG ACCGCGGGCA CGCTCTCCGC TG#CACTGAGC     60CCAGGGCTGC CGGCCTCTGC CGACCCCTGC TATGATGAAG CGAGGGAGCC TC#GCTCTTGT    120ATTCCTGGCC TTGTGAACGC TGCTCTGGGC CGAGAGGTGC TGGCGTCCAG CA#CGTGCGGG    180AGGTCGGCCA ATCGCGTCTG CGATTCCTCG GACCCGCAGC GGGCTCACTC TG#CAGACCTC    240CTGACCTCTG CTCCGGGCAC TGCAAGTCCT CTCTGTTGGC GCTCCGATTT GC#TGCAACAG    300GCACCTTTCA ACGTAACCCT CACAGTGCCC CTGGGGAAGG CTTTTGAGCT GG#TCTTCGTG    360AGCCTGCGCT TCTGCTCAGC TCCTCCAACC TCCGTGGCCC TGCTTAAGTC GC#AGGACCAT    420GGCCGCAGCT GGGTCCCCTT GGGCTTCTTC TCTTCCAGCT GTACCCTGGA CT#ATGGCCGT    480CTGCCTGCTC CTGCTGATGG CCCTTCTGGT CCAGGGCCAG AAGCCCTCTG CT#TTCCAGCC    540CCCCAGGCTC AGCCTGATGG TGGAGGCCTT CTGGCCTTCA GTGTGCAGGA TG#GCAGCCCA    600CAGGGCCTGG ATCTGGACAA CAGCCCCGTG CTCCAAGACT GGGTGACTGC CA#CAGATATT    660CGCATAGTAC TCACAAGGCC TGCCATTCAG GGAGACACCA GGGACGGTGG GG#TGACAGTC    720CCCTACTCCT ACTCAGCCAC TGAGCTTCAG GTGGGAGGTC GATGCAAGTG CA#ATGGGCAT    780GCCTCACGGT GTCTGTTGGA CACCCATGGC CACCTGGTCT GCGACTGCCA GC#ATGGTACA    840GAGGGCCCTG ATTGCAGCCG CTGCAAGCCC TTCTACTGCG ACAGGCCATG GC#AGCGGGCT    900ACAGGGCAGG AAGCCCACGC TTGCCTTGCT TGCTCCTGCA ACGGCCATGC GC#GAAGATGC    960CGCTTCAACA TGGAGCTCTA CCGACTGTCT GGCCGCCGCA GTGGGGGCGT GT#GCTCCAAC   1020TGCCGGCACA ATACAGCTGG TCGTCACTGC CACTACTGCC GGGAGGGCTT CT#ATCGTGAT   1080CCAGGCCGTG TCCTGAGTGA CCGTCGTGCT TGCAGAGCTT GTGACTGCCA CC#CAGTTGGT   1140GCTGCTGGCA AAACCTGTAA CCAGACCACA GGCCAGTGTC CCTGTAAGGA TG#GTGTTACT   1200GGCCTCACCT GTAACCGCTG TGCCCCAGGT TTCCAGCAGA GCCGTTCTCC TG#TGGCACCT   1260TGCGTTAAGA CTCCTGTCCC TGGACCCACC GAAGAAAGCA GTCCTGTGGA GC#CACAGGAC   1320TGTGAGTCAC ATTGCAGACC TGCGCGTGGC AGTTACCGAA TCAGCCTGAA GA#AGTTCTGC   1380CGGAAGGACT ATGCGGTGCA GGTGGCAGTG GGTGCACGCG GTGAGGCCCG CG#GCTCGTGG   1440ACACGCTTTC CGGTAGCGGT GCTTGCTGTG TTCCGCAGCG GCGAGGAACG CG#CTCGACGC   1500GGGAGCAGCG CGCTGTGGGT ACCAACCCTA GACGCGGCCT GCGGTTGCCC GC#GCCTCCTG   1560CCTGGCCGGC GTTACTTGCT GCTGGGAGGT GGGCCGGGGG CTGCAGCTGG GA#GCACAGCG   1620GGCCGGGGAC AGGGGCTCAG TGCTGCCCGT GGAAGCCTCG TGCTGCCTTG GA#GAGACGCC   1680TGGACCCGGC GCCTGCGGAG GCTGCAGAGG AGAGAGCGGC GGGGGCGCTG CG#GGACCGCC   1740 TGA                   #                  #                   #           1743 (2) INFORMATION FOR SEQ ID NO: 10:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 580 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #10:Met Pro Thr Trp Leu Trp Gly Leu Leu Leu Th #r Ala Gly Thr Leu Ser1               5    #                10   #                15Ala Ala Leu Ser Pro Gly Leu Pro Ala Ser Al #a Asp Pro Cys Tyr Asp            20       #            25       #            30Glu Ala Arg Glu Pro Arg Ser Cys Ile Pro Gl #y Leu Val Asn Ala Ala        35           #        40           #        45Leu Gly Arg Glu Val Leu Ala Ser Ser Thr Cy #s Gly Arg Ser Ala Asn    50               #    55               #    60Arg Val Cys Asp Ser Ser Asp Pro Gln Arg Al #a His Ser Ala Asp Leu65                   #70                   #75                   #80Leu Thr Ser Ala Pro Gly Thr Ala Ser Pro Le #u Cys Trp Arg Ser Asp                85   #                90   #                95Leu Leu Gln Gln Ala Pro Phe Asn Val Thr Le #u Thr Val Pro Leu Gly            100       #           105       #           110Lys Ala Phe Glu Leu Val Phe Val Ser Leu Ar #g Phe Cys Ser Ala Pro        115           #       120           #       125Pro Thr Ser Val Ala Leu Leu Lys Ser Gln As #p His Gly Arg Ser Trp    130               #   135               #   140Val Pro Leu Gly Phe Phe Ser Ser Ser Cys Th #r Leu Asp Tyr Gly Arg145                 1 #50                 1 #55                 1 #60Leu Pro Ala Pro Ala Asp Gly Pro Ser Gly Pr #o Gly Pro Glu Ala Leu                165   #               170   #               175Cys Phe Pro Ala Pro Gln Ala Gln Pro Asp Gl #y Gly Gly Leu Leu Ala            180       #           185       #           190Phe Ser Val Gln Asp Gly Ser Pro Gln Gly Le #u Asp Leu Asp Asn Ser        195           #       200           #       205Pro Val Leu Gln Asp Trp Val Thr Ala Thr As #p Ile Arg Ile Val Leu    210               #   215               #   220Thr Arg Pro Ala Ile Gln Gly Asp Thr Arg As #p Gly Gly Val Thr Val225                 2 #30                 2 #35                 2 #40Pro Tyr Ser Tyr Ser Ala Thr Glu Leu Gln Va #l Gly Gly Arg Cys Lys                245   #               250   #               255Cys Asn Gly His Ala Ser Arg Cys Leu Leu As #p Thr His Gly His Leu            260       #           265       #           270Val Cys Asp Cys Gln His Gly Thr Glu Gly Pr #o Asp Cys Ser Arg Cys        275           #       280           #       285Lys Pro Phe Tyr Cys Asp Arg Pro Trp Gln Ar #g Ala Thr Gly Gln Glu    290               #   295               #   300Ala His Ala Cys Leu Ala Cys Ser Cys Asn Gl #y His Ala Arg Arg Cys305                 3 #10                 3 #15                 3 #20Arg Phe Asn Met Glu Leu Tyr Arg Leu Ser Gl #y Arg Arg Ser Gly Gly                325   #               330   #               335Val Cys Ser Asn Cys Arg His Asn Thr Ala Gl #y Arg His Cys His Tyr            340       #           345       #           350Cys Arg Glu Gly Phe Tyr Arg Asp Pro Gly Ar #g Val Leu Ser Asp Arg        355           #       360           #       365Arg Ala Cys Arg Ala Cys Asp Cys His Pro Va #l Gly Ala Ala Gly Lys    370               #   375               #   380Thr Cys Asn Gln Thr Thr Gly Gln Cys Pro Cy #s Lys Asp Gly Val Thr385                 3 #90                 3 #95                 4 #00Gly Leu Thr Cys Asn Arg Cys Ala Pro Gly Ph #e Gln Gln Ser Arg Ser                405   #               410   #               415Pro Val Ala Pro Cys Val Lys Thr Pro Val Pr #o Gly Pro Thr Glu Glu            420       #           425       #           430Ser Ser Pro Val Glu Pro Gln Asp Cys Glu Se #r His Cys Arg Pro Ala        435           #       440           #       445Arg Gly Ser Tyr Arg Ile Ser Leu Lys Lys Ph #e Cys Arg Lys Asp Tyr    450               #   455               #   460Ala Val Gln Val Ala Val Gly Ala Arg Gly Gl #u Ala Arg Gly Ser Trp465                 4 #70                 4 #75                 4 #80Thr Arg Phe Pro Val Ala Val Leu Ala Val Ph #e Arg Ser Gly Glu Glu                485   #               490   #               495Arg Ala Arg Arg Gly Ser Ser Ala Leu Trp Va #l Pro Thr Leu Asp Ala            500       #           505       #           510Ala Cys Gly Cys Pro Arg Leu Leu Pro Gly Ar #g Arg Tyr Leu Leu Leu        515           #       520           #       525Gly Gly Gly Pro Gly Ala Ala Ala Gly Ser Th #r Ala Gly Arg Gly Gln    530               #   535               #   540Gly Leu Ser Ala Ala Arg Gly Ser Leu Val Le #u Pro Trp Arg Asp Ala545                 5 #50                 5 #55                 5 #60Trp Thr Arg Arg Leu Arg Arg Leu Gln Arg Ar #g Glu Arg Arg Gly Arg                565   #               570   #               575Cys Gly Thr Ala             580 (2) INFORMATION FOR SEQ ID NO: 11:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 727 amino #acids           (B) TYPE: amino acid           (C) STRANDEDNESS: single          (D) TOPOLOGY: linear     (ii) MOLECULE TYPE: peptide    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:  #11:Met Ile Arg Gly Ile Leu Leu Leu Leu Leu Gl #y Thr Thr Arg Phe Ser1               5    #                10   #                15Pro Ile Gln Cys Ile Phe Asn Asp Val Tyr Ph #e Lys Met Phe Ser Gln            20       #            25       #            30Gln Ala Pro Pro Glu Asp Pro Cys Tyr Asn Ly #s Ala His Glu Pro Arg        35           #        40           #        45Ala Cys Ile Pro Asp Phe Val Asn Ala Ala Ty #r Asp Ala Pro Val Val    50               #    55               #    60Ala Ser Ser Thr Cys Gly Ser Ser Gly Ala Gl #n Arg Tyr Cys Glu Tyr65                   #70                   #75                   #80Gln Asp His Glu Arg Ser Cys His Thr Cys As #p Met Thr Asp Pro Leu                85   #                90   #                95Arg Ser Phe Pro Ala Arg Ser Leu Thr Asp Le #u Asn Asn Ser Asn Asn            100       #           105       #           110Val Thr Cys Trp Arg Ser Glu Pro Val Thr Gl #y Ser Gly Asp Asn Val        115           #       120           #       125Thr Leu Thr Leu Ser Leu Gly Lys Lys Phe Gl #u Leu Thr Tyr Val Ile    130               #   135               #   140Leu Gln Leu Cys Pro His Ala Pro Arg Pro As #p Ser Met Val Ile Tyr145                 1 #50                 1 #55                 1 #60Lys Ser Thr Asp His Gly Leu Ser Trp Gln Pr #o Phe Gln Phe Phe Ser                165   #               170   #               175Ser Gln Cys Arg Arg Leu Phe Gly Arg Pro Al #a Arg Gln Ser Thr Gly            180       #           185       #           190Arg His Asn Glu His Glu Ala Arg Cys Ser As #p Val Thr Arg Pro Leu        195           #       200           #       205Val Ser Arg Ile Ala Phe Ser Thr Leu Glu Gl #y Arg Pro Ser Ser Arg    210               #   215               #   220Asp Leu Asp Ser Ser Pro Val Leu Gln Asp Tr #p Val Thr Ala Thr Asp225                 2 #30                 2 #35                 2 #40Ile Arg Val Val Phe His Arg Leu Gln Arg Pr #o Asp Pro Gln Ala Leu                245   #               250   #               255Leu Ser Leu Glu Ala Gly Gly Ala Thr Asp Le #u Ala Ser Gly Lys Tyr            260       #           265       #           270Ser Val Pro Leu Ala Asn Gly Pro Ala Gly As #n Asn Ile Glu Ala Asn        275           #       280           #       285Leu Gly Gly Asp Val Ala Thr Ser Gly Ser Gl #y Leu His Tyr Ala Ile    290               #   295               #   300Ser Asp Phe Ser Val Gly Gly Arg Cys Lys Cy #s Asn Gly His Ala Ser305                 3 #10                 3 #15                 3 #20Lys Cys Ser Thr Asp Ala Ser Gly Gln Leu As #n Cys Glu Cys Ser His                325   #               330   #               335Asn Thr Ala Gly Arg Asp Cys Glu Arg Cys Ly #s Pro Phe His Phe Asp            340       #           345       #           350Arg Pro Trp Ala Arg Ala Thr Ala Lys Glu Al #a Asn Glu Cys Lys Glu        355           #       360           #       365Cys Asn Cys Asn Lys His Ala Arg Gln Cys Ar #g Phe Asn Met Glu Ile    370               #   375               #   380Phe Arg Leu Ser Gln Gly Val Ser Gly Gly Va #l Cys Gln Asn Cys Arg385                 3 #90                 3 #95                 4 #00His Ser Thr Thr Gly Arg Asn Cys His Gln Cy #s Lys Glu Gly Phe Tyr                405   #               410   #               415Arg Asp Ala Thr Lys Pro Leu Thr His Arg Ly #s Val Cys Lys Ala Cys            420       #           425       #           430Asp Cys His Pro Ile Gly Ser Ser Gly Lys Il #e Cys Asn Ser Thr Ser        435           #       440           #       445Gly Gln Cys Pro Cys Lys Asp Gly Val Thr Gl #y Leu Thr Cys Asn Arg    450               #   455               #   460Cys Ala Arg Gly Tyr Gln Gln Ser Arg Ser Hi #s Ile Ala Pro Cys Ile465                 4 #70                 4 #75                 4 #80Lys Gln Pro Pro Arg Met Ile Asn Met Leu As #p Thr Gln Asn Thr Ala                485   #               490   #               495Pro Glu Pro Asp Ala Pro Glu Ser Ser Pro Gl #y Ser Gly Gly Asp Arg            500       #           505       #           510Asn Gly Ala Ala Glu Trp Pro Pro Ser Leu Se #r Thr Ile Ala Pro Arg        515           #       520           #       525Ala Ala Gly Val Lys Cys Gly Lys Cys Arg Va #l Ser Thr Lys Arg Leu    530               #   535               #   540Asn Leu Asn Lys Phe Cys Lys Arg Asp Tyr Al #a Ile Met Ala Lys Val545                 5 #50                 5 #55                 5 #60Ile Gly Arg Asp Thr Ser Ser Glu Ala Val Se #r Arg Glu Val Gln Arg                565   #               570   #               575Arg Ala Met Asp Pro Asp Val Ala Asp Tyr Gl #u Met Asp Gln Val Gln            580       #           585       #           590Pro Gly Ser Ala Arg Ser Pro Ile Thr Gly Va #l Tyr Glu Phe Gln Ala        595           #       600           #       605Ala Asp Tyr Pro Asn Pro Asn Pro Asn Pro Ar #g Gly Ser Glu Met Glu    610               #   615               #   620Arg Phe Asp Leu Gln Ile Gln Ala Val Phe Ly #s Arg Thr Arg Pro Gly625                 6 #30                 6 #35                 6 #40Glu Ser Ser Gly Ala Gly Asn Val Tyr Gly Me #t Pro Asn Thr Thr Leu                645   #               650   #               655Lys Arg Gly Pro Met Thr Trp Ile Ile Pro Th #r Lys Asp Leu Glu Cys            660       #           665       #           670Arg Cys Pro Arg Ile Arg Val Asn Arg Ser Ty #r Leu Ile Leu Gly Arg        675           #       680           #       685Asp Ser Glu Ala Pro Pro Gly Tyr Leu Gly Il #e Gly Pro His Ser Ile    690               #   695               #   700Val Ile Glu Trp Lys Glu Asp Trp Tyr Arg Ar #g Met Lys Arg Phe Gln705                 7 #10                 7 #15                 7 #20Arg Arg Ala Arg Thr Cys Ala                 725(2) INFORMATION FOR SEQ ID NO: 12:      (i) SEQUENCE CHARACTERISTICS:          (A) LENGTH: 110 base  #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: single           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #12: GGCCCGGAGT GCGACCGCTG CAAGCCCTTC CACTACGACC GGCCCTGGCA GC#GCGGCACA     60GCCCGCGAAG CCAACGAGTG CGTGGGTGAG TGGGGTGCGG CGGCGGACGG  #             110 (2) INFORMATION FOR SEQ ID NO: 13:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 106 base #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: single           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #13: CACACTTCGA CAACTCGCCC GTGCTGCAGG ACTGGGTCAC GGCCACAGAC AT#CCGCGTGG     60 CCTTCAGCCG CCTGCACTCG TTCGGCGACG AGAACAGACA CTCGGA   #                106 (2) INFORMATION FOR SEQ ID NO: 14:     (i) SEQUENCE CHARACTERISTICS:           (A) LENGTH: 273 base #pairs           (B) TYPE: nucleic acid          (C) STRANDEDNESS: single           (D) TOPOLOGY: linear    (ii) MOLECULE TYPE: cDNA     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: #14: CTCGAGAAGC TTCAGGACTA GGTAACGGCG ACCGACGTCC GTGTAGTGCT CA#CAAGGCCT     60AGCACGGCAG GTGACCCCAG GGACATGGAG GCCGTCGTCC CTTACTCCTA CG#CAGCCACC    120GACCTCCAGG TGGGCGGGCG CTGCAAGTGC AATGGACATG CCTCACGGTG CC#TGCTGGAC    180ACACAGGGCC ACCTGATCTG CGACTGTCGG CATGGCACCG AGGGCCCTGA CT#GCGGCCGC    240 TGCAAACCTT TTCACTTCGA CGGATCCCTC GAG       #                   #        273

What is claimed is:
 1. An isolated polypeptide comprising a portion ofSEQ ID NO:4, 6, 8, 10, or 11 of 25 residues in length, wherein thepeptide modulates neural axon outgrowth or orientation.
 2. The isolatedpolypeptide of claim 1, wherein the polypeptide comprises a portion ofSEQ ID NO:4 of 25 residues in length.
 3. The isolate polypeptide ofclaim 2, wherein the polypeptide comprises SEQ ID NO:4.
 4. The isolatedpolypeptide of claim 1, wherein the polypeptide comprises a portion ofSEQ ID NO:6 of 25 residues in length.
 5. The isolated polypeptide ofclaim 4, wherein the polypeptide comprises SEQ ID NO:6.
 6. The isolatedpolypeptide of claim 1, wherein the polypeptide comprises a portion ofSEQ ID NO:8 of 25 residues length.
 7. The isolated polypeptide of claim6, wherein the polypeptide comprises SEQ ID NO:8.
 8. The isolatedpolypeptide of claim 1, wherein the polypeptide comprises a portion ofSEQ ID NO:10 of 25 residues in length.
 9. The isolated polypeptide ofclaim 8, wherein the polypeptide comprises SEQ ID NO:10.
 10. Theisolated polypeptide of claim 1, wherein the polypeptide comprises aportion of SEQ ID NO:11 of 25 residues in length.
 11. The isolatedpolypeptide of claim 10, wherein the polypeptide comprises SEQ ID NO:11.12. The isolated polypeptide of claim 1, wherein the polypeptidecomprises an amino acid sequence selected from the group consisting ofSEQ ID NO:04, residues 289-294; SEQ ID NO:04, residues 296-304; SEQ IDNO:04, residues 308-315; SEQ ID NO:04, residues 320-338; SEQ ID NO:04,residues 345-350; SEQ ID NO:04, residues 352-368; SEQ ID NO:04, residues373-380; SEQ ID NO:04, residues 385-401; SEQ ID NO:04, residues 408-416;SEQ ID NO:04, residues 418-423; SEQ ID NO:04, residues 427-434; and SEQID NO:04, residues 439-451.
 13. The isolated polypeptide of claim 1,wherein the polypeptide comprises an amino acid sequence selected fromthe group consisting of SEQ ID NO:04, residues 454-460; SEQ ID NO:04,residues 466-478; SEQ ID NO:04, residues 485-499; SEQ ID NO:04, residues513-523; SEQ ID NO:04, residues 545-550; SEQ ID NO:04, residues 573-584;and SEQ ID NO:04, residues 528-537.
 14. The isolated polypeptide ofclaim 1, wherein the polypeptide comprises an amino acid sequenceselected from the group consisting of SEQ ID NO:04, residues 40-45; SEQID NO:04, residues 51-65; SEQ ID NO:04, residues 68-75; SEQ ID NO:04,residues 97-107; SEQ ID NO:04, residues 109-116 and SEQ ID NO:04,residues 117-123.
 15. The isolated polypeptide of claim 1, wherein thepolypeptide comprises an amino acid sequence selected from the groupconsisting of SEQ ID NO:06, residues 265-270; SEQ ID NO:06, residues272-280; SEQ ID NO:06, residues 284-291; SEQ ID NO:06, residues 296-319;SEQ ID NO:06, residues 328-344; SEQ ID NO:06, residues 349-356; SEQ IDNO:06, residues 361-371, SEQ ID NO:06, residues 384-392; SEQ ID NO:06,residues 394-399; SEQ ID NO:06, residues 403-410; and SEQ ID NO:06,residues 415-427.
 16. The isolated polypeptide of claim 1, wherein thepolypeptide comprises an amino acid sequence selected from the groupconsisting of SEQ ID NO:06, residues 429-435; SEQ ID NO:06, residues442-454; SEQ ID NO:06, residues 461-475; SEQ ID NO:06, residues 489-499;SEQ ID NO:06, residues 521-526; SEQ ID NO:06, residues 549-560; and SEQID NO:06, residues 504-513.
 17. The isolated polypeptide of claim 1,wherein the polypeptide comprises an amino acid sequence selected fromthe group consisting of SEQ ID NO:06, residues 27-30; SEQ ID NO:06,residues 38-52; SEQ ID NO:06, residues 55-62; SEQ ID NO:06, residues80-87 and SEQ ID NO:06, residues 88-94.
 18. The isolated polypeptide ofclaim 1, wherein the polypeptide comprises an amino acid sequence of SEQID NO:8, residues 451-456.